人群大脑结构差异遗传基础研究取得新进展
抑郁症是困扰人类的重大精神疾病之一，早期的双生子研究和领养研究证实，抑郁症是由遗传因素与外界环境共同作用的一种疾病。近年来，随着研究手段的不断成熟以及样本量的逐渐增大，越来越多的抑郁症易感基因被报道出来，然而绝大多数易感基因在中枢神经系统中的作用仍不甚清楚。
SLC6A15基因是首先在欧洲人群中通过全基因组关联分析发现的一个易感基因，位于SLC6A15基因区域的单核苷酸多态性位点（SNP）rs1545843在几份来自不同国家和地区的人群样本中均与抑郁症相关。同时，这个位点也被证实可以影响SLC6A15基因的mRNA表达，海马体积的变化以及神经元的完整性。不过，对于这个易感位点的研究仅限于此，其在中枢神经系统中的其它作用仍然不清楚。
研究表明，绝大多数精神疾病易感基因均可以影响脑结构的变化，而这种效应无论是在病人中还是健康人群中均存在。有鉴于此，中国科学院昆明动物研究所宿兵研究员实验室（李明博士）通过与复旦大学冯建峰教授的实验室合作，对来自昆明的包含278个健康个体的人群进行了脑部结构的核磁共振扫描（MRI），并在全脑范围内分析了rs1545843与脑区结构变化的关系。他们的研究结果发现，rs1545843与大脑中部扣带回体积显著相关（下图）。
众所周知，扣带回在大脑中主要参与情绪以及认知进程，而情绪及认知能力的改变是抑郁症患者的一个主要症状，并且有证据表明扣带回体积在抑郁症患者中发生了明显病变。因此，他们的研究结果进一步支持了SLC6A15基因在抑郁症发病中的作用，并且提示了其可能的致病机制。
该研究结果7月1日发表于国际精神病学刊物American Journal of Psychiatry（生物谷 Bioon.com）
生物谷推荐的英文摘要
Am J Psychiatry doi: 10.1176/appi.ajp.2013.12111458
Ming Li; Tian Ge; Jianfeng Feng; Bing Su
SLC6A15 rs1545843 and Depression: Implications From Brain Imaging Data
Major depression is a common neuropsychiatric disorder involving genetic components. A recent genome-wide association study identified a risk single-nucleotide polymorphism (SNP), rs1545843 in SLC6A15 (1), which encodes a sodium-dependent branched-chain amino acid transporter. The risk SNP also revealed associations with alterations in hippocampal volume, neuronal integrity, and SLC6A15 expression (1), but it remains unclear how rs1545843 affects brain development, causing deficits in a specific brain region and eventually leading to susceptibility to major depression.
An informative way of dissecting the functional role of the risk SNP is to test its associations with brain structures using in vivo MRI methods. We recruited 278 unrelated healthy Han Chinese individuals without alcohol dependence, mental disorders, drug abuse, or brain injury. Structural images were acquired using a 3-T Philips MRI scanner, and a voxel-based morphometry method was used to provide voxel-wise assessment of volumetric difference. Detailed information about the sample, MRI acquisition, image preprocessing, and genotyping methods are provided in the data supplement that accompanies the online edition of this letter. The effect of the genotype was examined using a linear regression at each voxel, adjusting for age, gender, and intracranial volume. Voxel-wise p values were corrected over the brain to control family-wise error rate.
We observed brain-wide significant association of rs1545843 with local gray matter volume in the median cingulate gyrus (family-wise error-corrected, voxel-wise p=0.031, cluster-wise p=0.0071, Figure 1). The cingulate cortex is a structurally heterogeneous brain region mainly involved in emotion and cognition processes (2), and deficits in patients with major depression have been frequently reported in this brain region. In addition, smaller regional gray matter volume of the cingulate gyrus has been observed in patients with major depression (3), although this has been more frequently reported in the anterior cingulate gyrus, while the median cingulate gyrus was rarely studied and the biological effects of this region on major depression are still unclear. However, we did not find a significant association in the hippocampus as described by Kohli et al. (1), and the discrepancy is possibly a result of sample difference. Patients with major depression and healthy comparison subjects were both evaluated in the Kohli et al. study, while we assessed only healthy individuals.
